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Inactivation of PP2A by a recurrent mutation drives resistance to MEK inhibitors

Oncogene volume 39, pages 703–717 (2020)Cite this article

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Abstract

The serine/threonine Protein Phosphatase 2A (PP2A) functions as a tumor suppressor by negatively regulating multiple oncogenic signaling pathways. The canonical PP2A holoenzyme comprises a scaffolding subunit (PP2A Aα/β), which serves as the platform for binding of both the catalytic C subunit and one regulatory B subunit. Somatic heterozygous missense mutations in PPP2R1A, the gene encoding the PP2A Aα scaffolding subunit, have been identified across multiple cancer types, but the effects of the most commonly mutated residue, Arg-183, on PP2A function have yet to be fully elucidated. In this study, we used a series of cellular and in vivo models and discovered that the most frequent Aα R183W mutation formed alternative holoenzymes by binding of different PP2A regulatory subunits compared with wild-type Aα, suggesting a rededication of PP2A functions. Unlike wild-type Aα, which suppressed tumorigenesis, the R183W mutant failed to suppress tumor growth in vivo through activation of the MAPK pathway in RAS-mutant transformed cells. Furthermore, cells expressing R183W were less sensitive to MEK inhibitors. Taken together, our results demonstrate that the R183W mutation in PP2A Aα scaffold abrogates the tumor suppressive actions of PP2A, thereby potentiating oncogenic signaling and reducing drug sensitivity of RAS-mutant cells.

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Acknowledgements

The authors wish to acknowledge the Young Scientist Foundation and the students who worked on this project through this program, including Aditya Upadhyay. This work was partially supported by the NIH/NCI R01CA181654 (to GN) and T32GM008803 (to CMO). This publication was made possible in part by the Clinical and Translational Science Collaborative of Cleveland, 4UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research. This research was supported by the Athymic Animal and Preclinical Therapeutics and Cytometry and Imaging Microscopy cores of the Case Comprehensive Cancer Center at Case Western Reserve University (funded by NIH P30 CA043703). GN is supported by the Pardee-Gerstacker Professorship in Cancer Research.

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Authors and Affiliations

  1. Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA

    Caitlin M. O’Connor

  2. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    Daniel Leonard, Sarah E. Taylor & Mark Jackson

  3. Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH, USA

    Danica Wiredja & Daniela Schlatzer

  4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Rita A. Avelar & Analisa DiFeo

  5. Department of Biological Structure, University of Washington, Seattle, WA, USA

    Zhizhi Wang & Wenqing Xu

  6. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Benjamin Bryson, Eesha Tokala, Aditya Upadhyay & Mark Jackson

  7. Department of Internal Medicine: Genetic Medicine, University of Michigan, Ann Arbor, MI, USA

    Jaya Sangodkar & Goutham Narla

  8. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada

    Anne-Claude Gingras

  9. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Anne-Claude Gingras

  10. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland

    Jukka Westermarck

  11. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Analisa DiFeo & Goutham Narla

  12. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA

    Analisa DiFeo

  13. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA

    David L. Brautigan

  14. Department of Pharmaceutical and Biological Chemistry, University College London, London, UK

    Shozeb Haider

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  1. Caitlin M. O’Connor
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Contributions

CMO and GN designed the research studies. CMO wrote the manuscript and GN edited the manuscript. CMO, DL, DW, RA, ZW, DS, BB, ET, AU, ST, and SH performed experiments and interpreted the data. JS, A-CG, JW, WX, AD, DB, SH, MJ, and GN provided observations and scientific interpretations. All authors discussed results and provided input on the manuscript.

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Correspondence to Goutham Narla.

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O’Connor, C.M., Leonard, D., Wiredja, D. et al. Inactivation of PP2A by a recurrent mutation drives resistance to MEK inhibitors. Oncogene 39, 703–717 (2020). https://doi.org/10.1038/s41388-019-1012-2

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